Multifunctional polymerized liposomes have been proposed for applications in medical sciences, such as bioimaging, diagnostics, drug delivery, and drug formulation. The multifunctional polymized liposomes have various functional moieties attached to a liposome core.
Methods have been described to prepare multiple functional polymerized liposomes with functional moieties that are either incorporated in the building blocks of the liposomes, or attached to an avidin moiety that binds to biotinated liposomes. In the case where functional moieties are incorporated in the liposome's building blocks, the ratio and density of the imaging and targeting agents in the polymerizable liposomes are limited by the phase diagram of the system.
However, when the functional moieties are attached to the avidin bound onto biotinylated liposomes, the loading is limited by the large size of avidin on the polymerizable liposome surface. Covering liposomes with avidin also increases non-specific binding and reduces the circulation time, both being important drawbacks for drug delivery, for example.
More recently, clickable liposomes have been described. However, in such cases, the liposomes were not polymerizable, and therefore not stable. The lack of stability significantly limits the development of non-polymerizable clickable liposomes for potentially relevant biomedical applications, as most liposomes used for diagnosis and drug delivery require a systematic optimization of the composition and density of many functional moieties on the liposome, which is challenging—if not impossible—to achieve on unstable non-polymerized liposomes.
The development of clickable polymerizable liposomes presents many challenges as the click chemistry between the molecular handles (ethynyl groups) and the moieties of interest with an azido group may not be compatible with the poly-diacetylene backbones of the clickable polymerized liposomes. Moreover, the use of conventional Cu(I) catalysts for click reaction causes oxidative degradation of unsaturated carbon-carbon bonds in liposomes, including the polydiacetylene backbones, typically leads to a leakage of the clickable polymerized liposome.
Click reactions performed with some of these materials have been reported (Binder 2007, Cavalli 2006, Gupta 2005, Hassane 2006, Lutz 2004, Opsteen 2007, Wang 2003) but the reactions were mostly performed in solvents containing at least one organic solvent such as ethanol, isopropanol, DMSO, or DMF. For the few examples of using click reactions to modify these materials in aqueous solutions, the reported catalysts (Chan 2004, Rodionov 2007) were less efficient than our catalysts based on the copper complex of the ligands 1-5 (Figure X) which are soluble in water.